Type 1 diabetes (T1D) arises from a breakdown in immune tolerance, where a chronic autoimmune attack results in the loss of pancreatic β-cells. It is becoming increasing apparent that T1D is associated with immune deficiency, rather than over-reactive immune responses. This is supported by genome-wide association studies (GWAS). For example, T1D patients are more likely to have genetic variants associated with reduced ability to regulate autoreactive T cell responses resulting from defects in T cell receptor (TCR) and aberrant cytokine signaling resulting from genetic defects in CD25, IL2, PTPN2, and PTPN22 (Lowe et al. (2007), Long et al. (2010), Rieck et al. (2007), Smyth et al. (2008)).
Although T1D is a major cause of morbidity and mortality worldwide, current treatment regimes for T1D have achieved only limited success. Immunomodulatory agents that transiently deplete T cells (anti-CD3, Rituximab) have only demonstrated temporary efficacy. Traditional vaccine strategies that involve the administration of autoantigen (e.g., insulin) alone also have failed to adequately block ongoing β-cell auto-immunity. Thus, improved treatment strategies that provide potent and long-term treatment effects are needed.
Regulatory T cells (Tregs) function as a dominant mediator of peripheral immune tolerance. Tregs suppress autoreactive T cell responses via various pathways, including attenuating inflammatory responses induced by antigen presenting cells (APCs) and activating anti-inflammatory biochemical pathways (Brusko et al. (2008)). Tregs create and maintain an anti-inflammatory milieu that fosters the establishment of immunological tolerance. Importantly, this protective effect can be transferred to T cells recognizing de novo antigens through the process of infectious tolerance (Jonuleit et al. (2002)).
Discovering the importance of Tregs in maintaining immune tolerance has opened a new means of therapeutic intervention—adoptive Treg therapy (Riley et al. (2009)). The efficacy of transferred. Tregs as a therapeutic modality has been demonstrated in animal models of systemic lupus erythematosus (SLE) (Scalapino et al. (2006)), multiple sclerosis (MS) (Kohm et al. (2002)), inflammatory bowel disease (IBD) (Nottet et al. (2003)), oophoritis (Setiady et al. (2006)), and T1D (Bluestone et al. (2004), Masteller et al. (2005), Tang et al. (2004)). However, a major limitation of adoptive Treg therapy is the decline of the transferred Treg population. One objective of the present invention is to provide improved adoptive Treg therapy for treating T1D and other immune disorders.